Intrinsic Capacity in Older Adults: Recent Advances

The global increase in the aging population is expected to result in a shift from disease-centered to function-centered approaches in response to intensive aging. Thus, the World Health Organization (WHO) has proposed a novel concept, intrinsic capacity (IC), which refers to the combination of one’s physical and mental abilities. The IC framework comprises cognition, mobility, psychological, vitality, and sensory functions. WHO also issued the Guidelines on Integrated Care for Older People (ICOPE) in 2017 and the Handbook: Guidance on person-centred assessment and pathways in primary carein 2019 to provide recommendations for community-level interventions and clinical practice, respectively. Recently, studies on the assessment of IC and verification of IC measurement have been proliferating. In this study, we reviewed the recent advances in IC research with older adults.

The global population is rapidly aging [1]. According to the World Health Organization (WHO), older adults aged ≥ 60 years will account for 12% in 2015 to 22% in 2050 (2 billion) of the world's population (www.who.int/newsroom/fact-sheets/detail/ageing-and-health). To formulate public health strategies in response to the aging population, WHO has proposed the concept of healthy aging as the process of developing and maintaining the functional ability required for the healthy life of older adults (apps.who.int/iris/handle/10665/186463). Functional ability depends on intrinsic capacity (IC) and the environment, as well as the interaction between them. IC refers to the sum of an individual's physical and mental abilities. Evidence shows that focusing on the IC of older adults is more effective than focusing on specific chronic diseases [2][3][4]. Therefore, WHO proposed Guidelines on Integrated Care for Older People (ICOPE) for the maintenance of IC (apps.who.int/iris/handle/10665/ 258981). However, research on IC assessment and on the development of interventions to improve IC is still in its infancy. This article reviews the progress of research on IC as well as its implications for clinical work.

Intrinsic capacity
The World Report on Ageing and Health by WHO proposed the novel concept of healthy aging, as the process of developing and maintaining the functional ability that enables well-being in old age (apps.who.int/iris/handle/10665/186463). Accordingly, functional ability is described as "the health-related attributes that enable people to be and to do what they have reason to value" [5]. Furthermore, IC refers to the sum of the physical and mental capacities of an individual, determining the functional ability combined with environmental factors and their interaction (apps.who.int/ iris/handle/10665/186463). Older adults can achieve higher quality of life in their later years, when they are within a suitable environment and have reached the peak of each health phase, thus reducing the burden of the society. The existing care model for older adults is to predict and respond to diseases by targeting specific disease markers. Wang et al [6] reviewed that the shift from disease-centered care to IC has major implications for nursing practice in older hospitalized adults. However, the new WHO care model of healthy aging involves a longitudinal observation of the individual's trajectory, with the goal of implementing active and personalized interventions that improve older adults' IC and functional ability (apps.who.int/iris/handle/10665/186463).

Research on the evaluation of intrinsic capacity
IC is a strong predictor for health outcomes from the perspective of function. There are several complex IC indicators; therefore, which of these can be used specifically to evaluate the overall physical and mental state of an individual? Cesari [7] used the International Classification of Functioning, Disability and Health framework as a base, combined it with available evidence, and identified the five IC domains (locomotion, vitality, cognition, psychological, and sensory) as the key to controlling and maintaining the IC of older adults, thereby permitting subsequent evaluation of IC. Similarly, Beard [8] assessed walking speed, chair-stand test, balance, grip strength, forced expiratory volume, blood assay, sensory, cognitive function, and sleep in the English Longitudinal Study on Ageing (ELSA) and found that five subfactors (psychological, sensory, cognitive, vitality, and locomotor) formed a structure to better predict future functioning, which is consistent with the findings of Cesari. A recent Chinese study also validated this structure using the same method as in ELSA [9]. Based on these studies, researchers from different countries have evaluated and verified the predictive value of the decline of IC and its domains in older adults. Table 1 presents the longitudinal studies on IC. Although diverse assessments of IC were employed in these studies, IC decline was commonly associated with adverse outcomes, such as falls, and deterioration in activities of daily living (ADLs) and instrumental activities of daily living (IADLs) [8][9][10][11][12][13]. Furthermore, a high IC score was associated with decreased risk of 1-year mortality [13]. Therefore, IC demonstrated strong potential to predict negative outcomes among older adults in different clinical settings. A general IC index, rather than simple effects of different subdomains added together, may provide better predicted value. Thus far, no global IC index has been validated for clinical or research purposes [14]. Therefore, more research on the validation of IC concepts and constructs is required, along with further quantitative evaluation of IC and its domains in different settings.

IC and frailty
IC, represents the amount of resources available to a person over a lifetime, is a dynamic concept, and its trajectory can provide information about the entire lifespan to clinical and public health activities, at an individual or a national level [15]. Clinicians can detect deviations from the norm before clinical manifestations, evaluate the effectiveness of interventions, and take preventive measures to achieve healthy aging. As a novel concept, IC has plenty of distinctions as well as commonalities and connections with frailty.
Frailty is a geriatric syndrome in which the gradual decline of an individual's physiological system makes the individual more susceptible to stressors and increases the risk of adverse health outcomes [15]. Furthermore, frailty is a condition that appears before the onset of disability, most often associated with the latter phase of life [16].
IC and frailty can be viewed as two sides of the same coin [10], where the former is an individual's reserve of ability, whereas the latter a hindrance that grows with aging. However, the two concepts are not mutually exclusive. Belloni [15] argued that IC, to some extent, can be considered as an evolution of the concept of frailty. The two concepts are complementary; monitoring IC can support the concurrent evaluation of individual frailty. Assessing the IC of a frail individual can also prove valuable, such as by resulting in the development of an individual, personalized care plan based on an individual's thoughts and priorities. Robledo [17] argued that the IC score acts as a determinant of frailty, pre-frailty, or robustness among adults, suggesting that the IC indices were significantly associated with frailty. Thus, further studies are needed to untangle the intricate relationship between IC and frailty.

IC and physical resilience
Physical resilience is a new concept in the field of geriatrics introduced by the National Institute on Aging (NIA) [18]; it is defined as the ability to recover from physically or psychologically traumatic events [19]. Consistent with IC, physical resilience also focuses on positive health attributes, and it targets function instead of diseases [20]. Chhetri [20] demonstrated that IC is a major determinant of physical resilience via physiological reserve. Therefore, we can assume that appropriate actions that improve IC can also improve physical resilience. However, more evidence and verification are required on this topic. Table 2 presents the comparisons among IC, frailty, and physical resilience.

Intrinsic capacity screening tools
The 2019 Integrated Care for the Elderly (ICOPE)-Guidance on person-centred assessment and pathways in primary care introduced by WHO prepared a quick and easy screening tool for IC. The WHO ICOPE screening tool for IC was validated among Chinese adults [21], which indicated that the proportion of decline in mobility, cognition, vitality, hearing, vision, and psychology was 25.3%, 46.8%, 16.2%, 15.4%, 11.7%, and 12.0%, respectively; furthermore, lower IC scores were associated with increasing age, slow walking speed, poor grip strength, and frailty [21]. This was the first study to validate the ICOPE screening tool, suggesting that the tool proposed by WHO can be effective in identifying people exhibiting decline in IC. A 2-year study with 212 adults aged ≥ 75 years validated this prediction for functional decline and fall [10]. Similarly, the Multidomain Alzheimer Preventive Trial, for older 759 adults (70-89 years old) with memory issues, reported that the frequencies of cognitive decline, limited mobility, malnutrition, visual impairment, hearing loss and depressive symptoms were 52.2%, 20.2%, 6.6%, 18.1%, 56.2%, and 39%, respectively, using the ICOPE screening tool [22]. Thus, we require additional validation studies with larger sample sizes that explore pragmatic ways to implement the ICOPE screening tool within various contexts.

Intrinsic capacity biomarkers
IC reflects an individual's biological aging process, and its evaluation may provide an innovative mechanism for encouraging adults to adopt healthy lifestyles.
Identification of potential biomarkers of IC decline may provide simple and objective measurements of an individual's biological age and health status and may guide the development of strategies to minimize IC decline, even delay progress toward disability [23]. However, research on the identification of IC biomarkers is rare. In a 5-year follow-up study, participants with elevated homocysteine or C-reactive protein (CRP) levels demonstrated a decrease in IC, and this decrease was more significant among those exhibiting higher CRP levels combined with hyperhomocysteinemia [24]. Moreover, participants with deteriorating IC reported significantly higher levels of plasma N-terminal pro-B-type Natriuretic Peptide (NT-proBNP) than those with normal IC, and the former were associated with abnormal mobility, hearing, vision, and psychological function [25]. In addition, increased serum tumor necrosis factor receptor 1 (TNFR1) levels were independently associated with reduced IC, suggesting that chronic inflammation may be the basis for decline in IC [26]. Based on this evidence, some studies have proposed lifestyle interventions [27][28][29] or supplements of omega-3 (ω-3) polyunsaturated fatty acid (PUFA)-known for its anti-inflammatory effects [30][31][32][33][34]-to mitigate the effects on cognitive impairment [27][28][29][30]34] and other domains [31][32][33]. However, a 3-year study with French communitydwelling participants, free of major neurocognitive disorders, reported no improvement in IC after undergoing ω-3 supplementation and multidomain lifestyle intervention [31][32][33]. Furthermore, no existing study has examined the effect on the decline in overall IC [35]. Therefore, further investigation is required on the biomarkers for IC decline and the development of interventions to delay overall IC decline.

ICOPE Handbook-Guidance on person-centred assessment and pathways in primary care
To address the adverse events due to the decline of IC, WHO issued the ICOPE guidelines to manage IC decline in 2017 (apps.who.int/iris/handle/10665/258981). Thirteen recommendations were provided, including reducing mobility loss, reducing malnutrition, maintaining visual and hearing ability, preventing cognitive decline and depression, management of agerelated conditions and falls, and provision of support to caregivers. WHO also published the Handbook: Guidance on person-centred assessment and pathways in primary care in 2019 to help community-health and care workers implement the ICOPE recommendations (apps.who.int/iris/handle/10665/326843). It outlines a healthcare pathway for managing critical health conditions associated with IC decline. Personalized care plans integrate strategies to reverse, delay, or prevent further decline.

The worldwide implementation of the ICOPE guidelines
Researchers from various countries have made innovative efforts to implement the ICOPE guidelines. The INStitute for Prevention healthy agIng and medicine REjuvenative (INSPIRE) initiative in France aimed to build a bioresource research platform for healthy aging by gathering biological, clinical, and digital resources to identify markers of aging, age-related diseases, and IC evolution [36,37]. Scientists plan to conduct a large-scale clinical survey of ICOPE using the ICOPE screening tool with older adults every 4 months for 10 years. INSPIRE will demonstrate the feasibility of screening and assessing IC level in primary care services, as well as conduct remote and long-term monitoring of this population's IC [38]. In collaboration with the INSPIRE program, Tavassoli [37] examined IC in 962 older adults from Occitania, in accordance with the 5-step ICOPE guidelines, and found that most older adults demonstrated a decline in at least one IC subdomain, with decline in vision, hearing, and cognitive function being most commonly reported. The ICOPE Monitor, a new technology derived from the INSPIRE program, has been developed to assess individuals' IC [36]. The ICOPE application is another tool developed by WHO [39]. These two applications are readily available free of charge in the Apple or Android Store [40]. China has proposed the "Medical and old-aged care integration model" as a strategy and implemented it as a policy in the recent years. China has incorporated the novel concept of healthy aging, put forth by WHO, into its existing care model and modified it to be peoplecentered so that older adults can both achieve healthy aging and enjoy their old life better [41]. Further research on the implementation of abovementioned new platform and technology within clinical settings and households is required.

Conclusion
Active management of the aging population has become a challenge. IC, the sum of all physical and mental functions, is of great value in predicting subsequent care dependence rather than the single or multiple disease investigation approach. To this end, WHO issued the ICOPE guidelines and handbook in 2017 and 2019, respectively, to aid primary healthcare workers, who provide care for older adults, using recommendations for the management and care of decline in different IC subdomains, as well as a care pathway for identifying and screening IC in order to assess, manage, and provide appropriate support to caregivers. Future research should focus on the development of interventions and integration of novel concepts in clinical and routine care provision for older adults.